Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p
Authors: Daniel J. Weiner, Emi Ling, Serkan Erdin, Derek J. C. Tai, Rachita Yadav, Jakob Grove, Jack M. Fu, Ajay Nadig, Caitlin E. Carey, Nikolas Baya, Jonas Bybjerg-Grauholm, Preben B. Mortensen, Thomas Werge, Ditte Demontis, Ole Mors, Merete Nordentoft, Thomas D. Als, Marie Baekvad-Hansen, Anders Rosengren, Alexandra Havdahl, Anne Hedemand, Aarno Palotie, Aravinda Chakravarti, Dan Arking, Arvis Sulovari, Anna Starnawska, Bhooma Thiruvahindrapuram, Christiaan de Leeuw, Caitlin Carey, Christine Ladd-Acosta, Celia van der Merwe, Bernie Devlin, Edwin H. Cook, Evan Eichler, Elisabeth Corfield, Gwen Dieleman, Gerard Schellenberg, Hakon Hakonarson, Hilary Coon, Isabel Dziobek, Jacob Vorstman, Jessica Girault, James S. Sutcliffe, Jinjie Duan, John Nurnberger, Joachim Hallmayer, Joseph Buxbaum, Joseph Piven, Lauren Weiss, Lea Davis, Magdalena Janecka, Manuel Mattheisen, Matthew W. State, Michael Gill, Mark Daly, Mohammed Uddin, Ole Andreassen, Peter Szatmari, Phil Hyoun Lee, Richard Anney, Stephan Ripke, Kyle Satterstrom, Susan Santangelo, Susan Kuo, Ludger Tebartz van Elst, Thomas Rolland, Thomas Bougeron, Tinca Polderman, Tychele Turner, Jack Underwood, Veera Manikandan, Vamsee Pillalamarri, Varun Warrier, Alexandra Philipsen, Andreas Reif, Anke Hinney, Bru Cormand, Claiton H. D. Bau, Diego Luiz Rovaris, Edmund Sonuga-Barke, Elizabeth Corfield, Eugenio Horacio Grevet, Giovanni Salum, Henrik Larsson, Jan Buitelaar, Jan Haavik, James McGough, Jonna Kuntsi, Josephine Elia, Klaus-Peter Lesch, Marieke Klein, Mark Bellgrove, Martin Tesli, Patrick W. L. Leung, Pedro M. Pan, Soren Dalsgaard, Sandra Loo, Sarah Medland, Stephen V. Faraone, Ted Reichborn-Kjennerud, Tobias Banaschewski, Ziarih Hawi, Sabina Berretta, Evan Z. Macosko, Jonathan Sebat, Luke J. O’Connor, David M. Hougaard, Anders D. Børglum, Michael E. Talkowski, Steven A. McCarroll, Elise B. Robinson
Journal: Nature Genetics (2022)

Abstract The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.